Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1

J Biol Chem. 2003 Dec 5;278(49):48720-6. doi: 10.1074/jbc.M306745200. Epub 2003 Sep 24.


In models of type 1 diabetes, cytokines induce pancreatic beta-cell death by apoptosis. This process seems to be facilitated by a reduction in the amount of the islet-brain 1/JNK interacting protein 1 (IB1/JIP1), a JNK-scaffold with an anti-apoptotic effect. A point mutation S59N at the N terminus of the scaffold, which segregates in diabetic patients, has the functional consequence of sensitizing cells to apoptotic stimuli. Neither the mechanisms leading to IB1/JIP1 down-regulation by cytokines nor the mechanisms leading to the decreased capacity of the S59N mutation to protect cells from apoptosis are understood. Here, we show that IB1/JIP1 stability is modulated by intracellular calcium. The effect of calcium depends upon JNK activation, which primes the scaffold for ubiquitination-mediated degradation via the proteasome machinery. Furthermore, we observe that the S59N mutation decreases IB1/JIP1 stability by sensitizing IB1/JIP1 to calcium- and proteasome-dependent degradation. These data indicate that calcium influx initiated by cytokines mediates ubiquitination and degradation of IB1/JIP1 and may, therefore, provide a link between calcium influx and JNK-mediated apoptosis in pancreatic beta-cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Apoptosis
  • Base Sequence
  • Calcium / metabolism*
  • Cell Line
  • Cysteine Endopeptidases / metabolism*
  • DNA Primers
  • Down-Regulation
  • Humans
  • Hydrolysis
  • Islets of Langerhans / cytology
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Multienzyme Complexes / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Point Mutation
  • Proteasome Endopeptidase Complex
  • Rats
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Ubiquitin / metabolism


  • Adaptor Proteins, Signal Transducing
  • DNA Primers
  • MAPK8IP1 protein, human
  • Mapk8ip1 protein, rat
  • Multienzyme Complexes
  • Nuclear Proteins
  • Trans-Activators
  • Ubiquitin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Calcium